Risperidone and paliperidone inhibit p-glycoprotein activity in vitro

Area of Science:

• Pharmacology
• Drug Transporter Research
• Neuroscience

Background:

• Risperidone (RSP) and its active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the P-glycoprotein (P-gp) efflux transporter.
• P-gp plays a crucial role in limiting the absorption and distribution of various drugs, including antipsychotics, by actively pumping them out of cells.
• Understanding the interaction of RSP and PALI with P-gp is essential for predicting their clinical efficacy and potential drug-drug interactions.

Purpose of the Study:

• To investigate the in vitro effects of risperidone (RSP) and paliperidone (PALI) on P-glycoprotein (P-gp)-mediated drug transport.
• To evaluate the potential of RSP and PALI to inhibit P-gp activity in cellular models relevant to drug absorption and blood-brain barrier (BBB) penetration.
• To assess the influence of RSP on the intestinal absorption and BBB transport of coadministered P-gp substrate drugs.

Main Methods:

• Inhibition of P-gp-mediated transport was assessed using rhodamine123 (Rh123) and doxorubicin (DOX) accumulation assays in LLC-PK1/MDR1 cells.
• Cellular uptake and efflux studies were conducted in Caco-2 cell monolayers and primary cultured rat brain microvessel endothelial cells (RBMECs) to model intestinal and BBB transport.
• Determination of IC(50) values for P-gp inhibition and measurement of apparent permeability coefficients (Papp) for Rh123 transport.

Main Results:

• Both RSP and PALI increased intracellular accumulation of Rh123 and DOX in a concentration-dependent manner, indicating P-gp inhibition.
• RSP demonstrated significant P-gp inhibitory activity with IC(50) values of 63.26 µM (Rh123) and 15.78 µM (DOX) in LLC-PK1/MDR1 cells, and 5.87 µM in Caco-2 cells.
• PALI was a less potent P-gp inhibitor (IC(50) >100 µM). RSP exposure increased Rh123 permeability across Caco-2 and RBMEC monolayers in the apical-to-basolateral direction and decreased it in the basolateral-to-apical direction.

Conclusions:

• Risperidone (RSP) and, to a lesser extent, paliperidone (PALI) inhibit P-glycoprotein (P-gp)-mediated transport in vitro.
• RSP has the potential to influence the intestinal absorption and blood-brain barrier (BBB) penetration of coadministered P-gp substrate drugs.
• RSP may increase the brain concentration of paliperidone by inhibiting P-gp-mediated efflux across the BBB.